Fig.

14 mean plasma phenacetin concentrations in six adult volunteers following administration

of 1.5g doses (in aqueous suspensions containing 200 mg of phenacetin per milliliter).
(from Ref.20.)

In the dissolution of drugs from coated dosage forms. Tablets or pellets of drugs contained
within tablets or capsules are coated for several reasons, as will be discussed in chapter 10.
Rationales for the use of coating include the need to protect a drug during storage or from the
very low pH of the stomach. Dosage forms may by coated so that they release their active
ingredients slowly for prolonged action. Some drugs are coated to protect the patient’s GIT from
local irritation. Whatever the reason, these coats are made from materials having various degrees
of hydrophilicity that may or may not break down and allow their active ingredients to dissolve.
Some poorly formulated coated tablets do not break down at all, and these dosage forms can be
recovered intact in the feces. Pharmacists must be aware of such pharmaceutical failures. They
must assure themselves that the particular dosage forms they are dispensing to their patients meet
all bioavailability standards, as discussed in chapter 3.
As illustrated in fig. 9, after a dosage form disintegrates into large particles, these large
particles must deaggregate to yield fine particles. Hence, deaggregation may be a rate-limiting
step in the dissolution process. Chloramphenicol plasma level versus time curves obtained ater
the oral administration to healthy volunteers of two 250-mg capsules of each of four different
brands of chloramphenicol are plotted in Fig. 15. The in vitro deaggregation rate of the same four
brands of chloramphenicol increased in the order D<B=C<A. Thus, the in vivo rate and extent of
availability of chloramphenicol from these capsule dosage forms correlates well with their in
vivo deaggregation rate.
Table 1 summarizes in vitro studies on the effect of pH, a potential patient variable, on
the dissolution rate of phenytoin from two different brands of capsules containing 100 mg of
sodium phenytoin. Preparation A retained its compact capsule shape no matter what the initial
pH of the dissolution medium. Moreover, the dissolution rate of phenytoin from preparation A
was pH-independent. Preparation B, however, broke down into fine particles. When the initial
pH was neutral, these particles rapidly dissolved. As the initial pH was lowered, these fine
particles precipitated. Since these precipitated particles then dissolved very slowly,it would
Drug Absorption and Availability

Fig. 15 Mean plasma levels for groups of ten human subjects receiving single 0,5-g doses (as
two 250-mg capsules) of chloramphenicol: preparations A,B,C, or D. vertical lines represent one
standard error on either side of the mean.(From Ref 21.)

Appear that the precipitate was not the freely soluble sodium phenytoin, but the poorly soluble
acid form of phenytoin. Since capsule A did not disintegrate or deaggregrate, most of the sodium
phenytoin was not exposed to the lower pH media and, as a result, was not converted to its very
slowly dissolving acid form.
Effect of manufacturing processes
Various manufacturing processes can affect dissolution by altering the effective surface area of
drug particles. Each of the individual processes mentioned here is discussed in more detail in
chapter 9. The effect of adding hydrophilic granulating agents to a dosage form has been
discussed earlier (see sec. III.A).
Lubricating agents are often added to capsule or tablet dosage forms so that the powder
mass or the finished dosage forms will not stick to the processing machinery. When the
hydrophilic lubricating agent sodium lauryl sulfate was added, 325-mg salicylic acid tablets
disolved in 0,1 N HCl more rapidly than did control tablets containing no lubricant, as shown

Table 1. in vitro Dissolution characteristicsa of two commercial phenytoin sodium capsule

Preparations
Time for 50% dissolution (min);
average of five capsules (SD)
Solvent system Initial pH Preparation A Preparation B
175 ml 0.1 N HCL and 175 ml 0.1 N NaOH ~7 42.4 (5.6) 12.3 (3.2)
175 ml 0.1 N HCL for 30 min, then addition
of 175 ml 0.1 N NaOH ~1 34.9b (5.6) 80.0b (26.2)
175 ml 0.01 N HCL for 30 min, then
addition of 175 ml 0.01 N NaOH ~2 32.6b (10.4) 25.2b (8.6)

a
Modifed Levy-Hayes method, 55 rpm,17˚C.
b
Time after addition of NaOH; less than 5% dissolved in HCL solution.
Source: Ref.22.
In Fig.16. if, however, the hydrophobic lubricant magnesium stearate was added, the dissolution
rate decreased. Most lubricants, and all the effective lubricants, are very hydrophobic, and they
act by particle coating. Thus they must be property formulated to avoid reducing dissolution rate
and bioavailability. Once again, increasing hydrophilicity of a dosage form enhanced its
dissolution rate in an aqueous medium, but increasing its hydrophobicity decreased its
dissolution rate.
Disintegrating agents, such as starch, tend to swell with wetting. In swelling the starch
can break apart the dosage form. As seen in Fig.17, again for 325-mg salicylic acid tablets, as
more starch was added to the tablets the drug dissolved more quickly because the dosage form
disintegrated more quickly.
The possible effects on dissolution rate of the force used in compressing the drug-diluent
mixture into a tablet dosage form have been summarized in Fig. 18. As compression force is
increased, the particles may be more tightly bound to one another. (part I of Fig. 18 best
represents this possibility.) on the ther hand, it is also possible that higher pressures may fracture
the particles so that the break into yet smaller particles (see part III of Fig. 18). Depending on
which of these two extremes is dominant for a given formulation, any of the combinations
illustrated in Fig. 18 is possible. Furthermore, a sum of any of them may result. Thus, the effect
of the compression force on the dissolution rate of a tablet dosage form would appear to be
unpredictable.
The packing density, as illustrated in Fig. 19, may affect the rate of release of a drug (not
identified in these studies) from a capsules dosage form [25]. For the rapidly dissolving
formulation (see Fig. 19a), packing density had no effect on release rate. For the slowly
dissolving formulation (see Fig. 19b), however, increasing packing density decreased dissolution
rate. It is probable that further studies of the effect of packing density on dissolution rate for
different

Fig. 16 effect of lubricant on dissolution rate of salicylic acid contained in compressed tablets. ×,
3% magnesium stearate; •, no lubricant; o, 3% sodium lauryl sulfate. (From Ref.23.)
Fig. 17 effect of starch content of granules on dissolution rate of salicylic acid contained in
compressed tablets. o, 5%; •, 10%; × 20% starch in granules. (Form Ref.24.)

Fig. 18 effect of compression pressure on dissolution rate. See the text for an explanation. (From
Ref.19.)

Fig. 19 influence of packing density on dissolution of drug from capsules in simulated gastric
fluid. ×, regular packing: 355mg/No.2 capsule;o, dense packing: 400mg/No.2 capsule.
(a)Drug,CaHPO4; (b)Drug, CaHPO4, 5% magnesium stearate. (From Ref.25.)
Drugs from different formulations would result in both increasing and decreasing dissolution
rates.
From the very few studies discussed here, of the many that have been published, it would
appear that manufacturing processes can determine the dissolution rate of a drug from its final
dosage form. Whether changes in these manufacturing variables are beneficial or detrimental to
the ultimate bioavailability of a drug depends on the physicochemical properties of the drug and
its dosage form. Pharmacists should be aware of the possible effects that “inert” ingredients and
manufacturing methods, which are usually carefully guarded trade secrets, may have on the
bioavailability of the drug products they select to dispense to their patients.
B. Saturation Solubility of the Drug, Cs
The next term in Eq. (1) that can be manipulated is Cs, the saturation solubility of the drug. This
variable can be influenced by both patient and pharmaceutical variables. The patient variables
include the changes in pH as well as the amounts and types of secretions along the GIT.
Additionally, both the physical and chemical properties of a drug molecule can be modified to
increase or decrease its saturation solubility.
Salt Form of the Drug
Since the salt form of a drug is more soluble in an aqueous medium, the dissolution rate for the
salt form of a drug should be greater than the dissolution rate of the non ionized form of the drug.
However , the solubility of the salt depends on the counterion; generally; the smaller the
counterion, the more soluble the salt. If dissolution is the rate-determining step in absorption,
then, for a series of salts and the non ionized form of a drug, it can be anticipated that the rate of
availability of the drug will increase as solubility increases. The weakly acidic drug p-amino
salicylic acid (PAS) is available as the potassium, calcium, or sodium salt. The solubility of non
ionized PAS is 1 g/600 ml of water; of KPAS, 1g/10 ml; of CaPAS, 1g/7ml; and of NaPAS,
1g/2ml. Healthy adult volunteers took, on a fasting stomach with 250ml of water, tablets
containing either 4 g of PAS or tablets containing 4 g of one of the salts(containing 2.6-2.8 g of
PAS) [26]. Mean plasma concentrations (corrected to a 4-g dose of PAS) versus time curves are
shown in Fig.20. Although the rates of availability of the salt are not significantly different, their
rank order does correlate with solubility. All the salt forms were more rapidly available than the
non ionized PAS to a significant extent. Furthermore, the extent of availability of the acid form is
only about 77% of that of the salt forms, indicating that the drug may not have completely
dissolved before the dosage form moved through the GIT. Since commercial tablets were used, it
is probable that other dosage form variables (as discussed in sec. III.A) were not held constant.
Thus, the decrease in rate and extent of availability of the PAS may not be exclusively due to
differences in solubility.
pH Effect
As indicated, the ionized form of a drug will be more soluble than the non ionized form in the
aqueous fluids of the GIT. The classic studies on the beneficial effects of changing non ionized
drugs into salt forms were reported by Nelson for tetracycline [27], and Nelson et al. for
tolbutamide [28]. Table 2 combines portions of the data from each study. Urinary excretion of
the drug or its metabolite was taken as the in vivo measure of the relative absorption rate for the
salt and the non ionized form of each drug. No comparison can be made between the two drugs,
and they are combined here only to illustrate that the same principles hold for both positively
and negatively charged drug ions. Note that the salt forms of the drug dissolve much faster than
the non ionized forms (or zwitterions for tetracycline) in all media and that more of the salt
forms of the drug are absorbed and subsequently excreted in each period. For a dis-